Multicellular living organisms and unmodified parts thereof and – Method of using a transgenic nonhuman animal in an in vivo...
Reexamination Certificate
2000-08-14
2003-05-13
Yucel, Remy (Department: 1636)
Multicellular living organisms and unmodified parts thereof and
Method of using a transgenic nonhuman animal in an in vivo...
C800S012000, C800S018000
Reexamination Certificate
active
06563015
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced by number. Full citations for these publications may be found listed at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
The pain of Alzheimer's disease results directly from the memory loss and cognitive deficits suffered by the patient. These eventually result in the patient's loss of identity, autonomy, and freedom. As a step toward curing this disease, alleviating its symptoms, or retarding its progression, it would be desirable to develop a transgenic animal model exhibiting the main debilitating phenotype of Alzheimer's disease, that is, memory loss, expressed concomitantly with the neuropathological correlates of Alzheimer's disease, for example, beta-amyloid accumulation, increased glial reactivity, and hippocampal cell loss.
It is estimated that over 5% of the U.S. population over 65 and over 15% of the U.S. population over 85 are beset with some form of Alzheimer's disease (Cross, A. J., Eur J Pharmacol (1982) 82:77-80; Terry, R. D., et al., Ann Neurol (1983) 14:497-506). It is believed that the principal cause for confinement of the elderly in long term care facilities is due to this disease, and approximately 65% of those dying in skilled nursing facilities suffer from it.
Certain facts about the biochemical and metabolic phenomena associated with the presence of Alzheimer's disease are known. Two morphological and histopathological changes noted in Alzheimer's disease brains are neurofibrillary tangles (NFT) and amyloid deposits. Intraneuronal neurofibrillary tangles are present in other degenerative diseases as well, but the presence of amyloid deposits both in the interneuronal spaces (neuritic plaques) and in the surrounding microvasculature (vascular plaques) seems to be characteristic of Alzheimer's. Of these, the neuritic plaques seem to be the most prevalent (Price, D. L., et al., Drug Development Research (1985) 5:59-68). Plaques are also seen in the brains of aged Down's Syndrome patients who develop Alzheimer's disease.
SUMMARY OF THE INVENTION
The present invention provides for a transgenic non-human transgenic animal whose cells contain a recombinant DNA sequence comprising: (a) a nerve tissue specific promoter operatively linked to a DNA sequence which encodes human receptor for advanced glycation endproducts (RAGE), and (b) a nerve tissue specific promoter operatively linked to a DNA sequence encoding a mutant human amyloid precursor protein hAPP695, hAPP751 and hAPP770 bearing mutations linked to familial Alzheimer's disease in humans, wherein said non-human transgenic animal exhibits at least one phenotype from the group consisting of: increased expression of M-CSF gene in cerebral cortex; increased expression of IL-6 gene in cerebral cortex; increased neuronal stress; increased neurotoxicity; neuron loss; increased level of activated form of caspase 3 in brain; and increased level of phosphorylated tau protein in brain.
REFERENCES:
Mullins et al., Transgenesis in Nonmurine Species, 1993, Hypertension, vol. 22, pp. 630-633.*
Selkoe, In the beginning, Dec. 12, 1991, Nature, vol. 354, pp. 432-433.*
Marx, Major Setback for Alzheimer's Models, Mar. 6, 1992, vol. 255, Science, pp. 1200-1202.*
Biotechnology Newswatch, Aug. 5, 1991, vol. 11, No. 15, pp. 3-4.*
Lannfelt et al., Alzheimer's disease: molecular gentics and transgenic animal models, 1993, Behaviroural Brain Research, vol. 57, pp. 207-213.*
Brett J, Schmidt A-M, Zou Y-S, Yan S-D, Weidman E, Pinsky DJ, Neeper M, Przysiecki M, Shaw A, Migheli A, Stern DM: Tissue distribution of the receptor for advanced glycation endproducts (RAGE): expression in smooth muscle, cardiac myocytes, and neural tissue in addition to Vasculature. Am J Pathol 1993; 143:1699-1712. (Exhibit 1).
Connolly E, Winfree C, Prestigiacomo C, Kim S, Choudri T, Hoh B, Naka Y, Solomon R, Pinsky D: Exacerbation of cerebral injury in mice with express the P-selection gene: identification of P-selection blockade as a new target for treatment of stroke. Circ Res 1997;81:304-310. (Exhibit 2).
Connolly ESJ, Winfree CJ,Springer TA, Naka Y, Liao H, Yan SD, Stern DM, Solomon RA, Gutierrez-Ramos J-C, Pinksy DJ: Cerebral Protection in homozygous null ICAM-1 mice a after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis in the pathogenesis of stroke. J Clin Invest 1996;97:209-216. (Exhibit 3).
Connolly ES, Winfree CJ, Stern DM, Solomon RA, Pinsky DJ: Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia. Neurosurg. 1996: 523-532. (Exhibit 4).
Hori O, Brett J, Nagashima M, Nitecki D, Morser J, Stern DM, Schmidt AM: RAGE is a cellular binding site for amphoterin: mediation of neurite outgrowth and co-expression of RAGE and amphoterin in the developing nervous system. J Biol chem 1995; 270: 25752-25761. (Exhibit 5).
Hoffman M, Drury S, Caifeng F, Qu W, Lu Y, Avila C, Kambhan N, Slattery T, McClary J, Nagashima M, Morser J, Stern D, Schmidt A-M: RAGE mediates a novel proinflammatory axis: the cell surface receptor for S100/calgranulin polypeptides. Cell 1999; 97: 889-901. (Exhibit 6).
Hsia A, Masliah E, McConlogue L, Yu G-Q, Tatsuno G, Hu K, Kholodenko D, Malenka R, Nicoll R, Mucke L: Plaque-independent distruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci (USA) 1999;96:3228-3233. (Exhibit 7).
Huang J, Kim L, Mealey R, March H, Zhang A, Tenner E, Connolly E, Pinsky D: Neuronal Protection in stroke by an sLex-glycosylated complement inhibitory protein. Science 1999;285:595-599. (Exhibit 8).
Nakashima Y, Plump A, Raines E, Breslow J, Ross R: ApoE-deficient mice develop lessions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 1994; 14:133-140. (Exhibit 9).
Park, L., et al. (1998) “Suppression of accelerated diabetic atherosclerosis by soluble Receptor for AGE (sRAGE)” Nature Medicine, 4:1025-1031. (Exhibit 10).
Schmidt, A.M., Yan S-D, Wautier J-L, Stern DM: Activation of RAGE:a mechanism for chronic dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 1999;489-497 (Exhibit 11).
White A, Zheng H, Galatis D, Maher F, Hesse L, Multhaup G, Beyreuther K, Masters C, Cappai R: Survival of cultered neurons from amyloid precursor protein knock-out mice against Alzheimer's amyloid-&bgr; toxicity and oxidative stress. J. Neurosci 1998; 18: 6207-6217. (Exhibit 12).
Yan S-D, Chen X, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern DM, Schmidt A-M: RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 1996; 382:685-691. (Exhibit 13).
Yan S-D, Zhu H, Zhu A, Golabek A, Roher A, Yu J, Soto C, Schmidt A-M, Stern DM, Kindy M: Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med 2000; 6:643-651. (Exhibit 14).
Yan S-F, Tritto I, Pinsky DJ, Liao H, May L, Stern DM: Induction of interleukin 6 (IL-6) by hypoxia in vascular cells: central role of the binding site for nuclear factor-IL-6. J. Biol chem 1995;270:11463-11471. (Exhibit 15).
Schmidt Ann Marie
Stern David M.
Yan Shi Du
Qian Celine
The Trustees of Columbia University in the City of New York
White John P.
Yucel Remy
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